ABSTRACT Previous studies have demonstrated that heart failure triggers and sustains increases in oxidative stress, inducing mitochondrial DNA (mtDNA) damage that then propagates myocardial injury resulting in cardiac dysfunction and myocardial cell death. Fortunately, mtDNA injury is reparable via endogenous base excision repair (BER) mechanisms. The rate-limiting step within BER is the amount of glycosylase present. Here we offer the novel therapeutic, Exscien1-III to catalyze and enhance mtDNA repair by trafficking to the mitochondria the glycosylase necessary to overcome this first and rate-determining stage, and thereby disrupt the propagation of myocardial disease. Exscien1-III is an innovatively engineered and patented, three-part fusion protein construct consisting of a TAT sequence (to facilitate cell uptake), a mitochondrial import sequence (to direct the therapeutic into the mitochondria) and a functional glycosylase (to help effect mtDNA repair). Exscien?s research variation of the protein also contains an HA tag for experimental immunological localization. Preliminary in vivo studies at LSU?s Cardiovascular Center of Excellence have demonstrated significant cardioprotective action using Exscien1-III in murine models of acute myocardial infarction (AMI) and heart failure (HF). The protein significantly attenuated myocardial infarct size and improved left ventricular function following myocardial ischemia and reperfusion in mice. Administration of Exscien1-III following the onset of severe HF attenuated myocardial fibrosis and left ventricular dilatation while improving left ventricular function in a murine pressure overload HF model. To further advance this fusion protein as an ameliorative therapeutic for HF, we seek to conduct a phased developmental program: Phase I - perform large animal efficacy, dosing and disposition testing of Exscien1-III; Phase II - utilize the results of Phase I to demonstrate efficacy of Exscien1-III, first as a therapy to prevent progression to HF following AMI and secondly, as a therapy to treat progressive HF in swine compromised with reduced ejection fraction. If successful, the evidence would form the foundation of an IND application to the FDA. Our commercialization objective is to develop the drug in-house as far as feasible (including planned early clinical trials), before ultimately out-licensing to a large pharmaceutical interest. With an estimated worldwide diagnosis of progressive heart failure in excess of 20 million, this therapy offers substantial commercial potential and has already attracted large ?pharma? interest.